Conformation-Activity Relationships

描述(由申请者提供)：我们的整个项目对聚酮类天然产物的进化的基本问题感兴趣。这些研究的重点是从两个相辅相成的角度。第一类是关于聚酮类化合物的特殊结构特征，它们对构象的影响，以及构象对生物活性的重要性。第二种观点侧重于结构上相关的多酮及其蛋白质靶标的共同进化。聚酮类天然产物由于其复杂的结构和多样的生物活性，是这些研究的理想对象，已显示出对一些治疗领域的研究和治疗有用。在之前的研究中，我们已经证明构象是对经典构效关系的重要补充，并为未来化疗药物的开发提供了有用的信息。作为原理的证明，对稳定微管的天然产物--埃博西酮的构象-活性关系的研究，提供了关于药效团的重要信息以及进一步开发的新线索。在接下来的资助期间，我们的研究将探索三个基本独特的项目：1.鬼臼糖苷A的构象-活性关系；2.凋亡素与结构上相关的多环大环内酯类化合物、巴非霉素和刀豆素之间的进化关系的研究；3.前体导向的生物合成技术的发展，以制备复杂的聚酮类似物。将通过独特而实用的合成策略来制备这一应用中针对的复杂天然产品。此外，在适当的情况下，我们还开发了一些新的合成方法，用于制备聚酮类天然产物常见的复杂结构单元。

DESCRIPTION (provided by applicant): Our overall program is interested in the fundamental issues regarding the evolution of polyketide natural products. The focus of these studies is from two complementary perspectives. The first deals with specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. The second perspective focuses on structurally related polyketides and the co-evolution of their protein targets. Polyketide natural products are ideal subjects for these studies due to their complex structure and diverse biological activities which have shown utility towards the study and treatment of a number of therapeutic areas. During the previous research period we have shown that conformation is an important complement to classic structure-activity relationships and provides useful information for the development of future chemotherapeutic agents. As a proof of principle, a conformation-activity relationship study of the microtubule-stabilizing natural products, the epothilones, provided important information with regards to the pharmacophore as well as new leads for further development. During the next grant period, our studies will investigate three fundamentally unique projects, 1. Conformation-activity relationships of peloruside A, 2. a study of the evolutionary relationship between apoptolidin and structurally related plecomacrolides, bafilomycin and concanamycin, and 3. The development of precursor-directed biosynthetic techniques for the preparation of complex polyketide analogues. The complex natural products targeted in this application will be prepared via unique but practical synthetic strategies. Moreover, where appropriate, we have incorporated the development of a number of new synthetic methods for the preparation of complex structural units common to polyketide natural products.